Holden P, Meadows R S, Chapman K L, Grant M E, Kadler K E, Briggs M D
Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Road., Manchester M13 9PT, United Kingdom.
J Biol Chem. 2001 Feb 23;276(8):6046-55. doi: 10.1074/jbc.M009507200. Epub 2000 Nov 21.
Cartilage oligomeric matrix protein (COMP) and type IX collagen are key structural components of the cartilage extracellular matrix and have important roles in tissue development and homeostasis. Mutations in the genes encoding these glycoproteins result in two related human bone dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia, which together comprise a "bone dysplasia family." It has been proposed that these diseases have a similar pathophysiology, which is highlighted by the fact that mutations in either the COMP or the type IX collagen genes produce multiple epiphyseal dysplasia, suggesting that their gene products interact. To investigate the interactions between COMP and type IX collagen, we have used rotary shadowing electron microscopy and real time biomolecular (BIAcore) analysis. Analysis of COMP-type IX collagen complexes demonstrated that COMP interacts with type IX collagen through the noncollagenous domains of type IX collagen and the C-terminal domain of COMP. Furthermore, peptide mapping identified a putative collagen-binding site that is associated with known human mutations. These data provide evidence that disruptions to COMP-type IX collagen interactions define a pathogenetic mechanism in a bone dysplasia family.
软骨寡聚基质蛋白（COMP）和IX型胶原蛋白是软骨细胞外基质的关键结构成分，在组织发育和内稳态中发挥重要作用。编码这些糖蛋白的基因突变会导致两种相关的人类骨发育不良疾病，即假性软骨发育不全和多发性骨骺发育不良，它们共同构成一个“骨发育不良家族”。有人提出，这些疾病具有相似的病理生理学机制，这一事实凸显了这一点，即COMP基因或IX型胶原蛋白基因的突变都会导致多发性骨骺发育不良，这表明它们的基因产物相互作用。为了研究COMP与IX型胶原蛋白之间的相互作用，我们使用了旋转阴影电子显微镜和实时生物分子（BIAcore）分析。对COMP-IX型胶原蛋白复合物的分析表明，COMP通过IX型胶原蛋白的非胶原结构域和COMP的C末端结构域与IX型胶原蛋白相互作用。此外，肽图谱分析确定了一个与已知人类突变相关的假定胶原结合位点。这些数据提供了证据，表明COMP与IX型胶原蛋白相互作用的破坏定义了一个骨发育不良家族中的致病机制。
